A principal mechanism for the cancer chemopreventive activity of phenethyl isothiocyanate is modulation of carcinogen metabolism

References

• Abdull Razis AF, Bagatta M, De Nicola GR, et al. (2011). Induction of epoxide hydrolase and glucuronosyl transferase by isothiocyanates and intact glucosinolates in precision-cut rat liver slices. Arch Toxicol 85:919–927
   PubMed Web of Science ®Google Scholar
• Abdull Razis AF, Bagatta M, De Nicola GR, et al. (2012). Characterization of the temporal induction of xenobiotic-metabolizing enzymes by glucosinolates and isothiocyanates: Requirement for at least a 6 h exposure to elicit complete induction profile. J Agric Food Chem 60:5556–5564
   PubMed Web of Science ®Google Scholar
• Abdull Razis AF, Noor NM, Konsue N. (2014). Induction of epoxide hydrolase, glucuronosyl transferase, and sulfotransferase by phenethyl isothiocyanate in male Wistar albino rats. Biomed Res Int 2014:391528
   Web of Science ®Google Scholar
• Adam-Rodwell G, Morse MA, Stoner GD. (1993). The effects of phenethyl isothiocyanate on benzo[a]pyrene-induced tumors and DNA adducts in A/J mouse lung. Cancer Lett 71:35–42
   PubMed Web of Science ®Google Scholar
• Al Janobi AA, Mithen RF, Gasper AV, et al. (2006). Quantitative measurement of sulforaphane, iberin and their mercapturic acid pathway metabolites in human plasma and urine using liquid chromatography-tandem electrospray ionisation mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 844:223–234
   PubMed Web of Science ®Google Scholar
• Ambrosone CB, McCann SE, Freudenheim JL, et al. (2004). Breast cancer risk in premenopausal women is inversely associated with consumption of broccoli, a source of isothiocyanates, but is not modified by GST genotype. J Nutr 134:1134–1138
   PubMed Web of Science ®Google Scholar
• Aras U, Gandhi YA, Masso-Welch PA, Morris ME. (2013). Chemopreventive and anti-angiogenic effects of phenethyl isothiocyanate in an N-methyl nitrosourea breast cancer animal model. Biopharm Drug Dispos 34:98–106
   PubMed Web of Science ®Google Scholar
• Baasanjav-Gerber C, Monien BH, Mewis I, et al. (2011). Identification of glucosinolate congeners able to form DNA adducts and to induce mutations upon activation by myrosinase. Mol Nutr Food Res 55:1–10
   Web of Science ®Google Scholar
• Barve A, Khor TO, Keum YS, et al. (2008). Murine prostate cancer inhibition by dietary phytochemicals-curcumin and phenethyl isothiocyanate. Pharm Res 25:2181–2189
   PubMed Web of Science ®Google Scholar
• Bonnesen C, Eggleston IM, Hayes JD. (2001). Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res 61:6120–6130
   PubMed Web of Science ®Google Scholar
• Boysen G, Kenney PM, Upadhyaya P, et al. (2003). Effects of benzyl isothiocyanate and 2-phenethyl isothiocyanate on benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism in F-344 rats. Carcinogenesis 24:517–525
   PubMed Web of Science ®Google Scholar
• Brown BG, Borschke AJ, Doolittle DJ. (2003). An analysis of the role of tobacco-specific nitrosamines in the carcinogenicity of tobacco smoke. Nonlinearity Biol Toxicol Med 1:179–198
   PubMedGoogle Scholar
• Cheung KL, Khor TO, Huang MT, Kong AN. (2010). Differential in vivo mechanism of chemoprevention of tumor formation in azoxymethane/dextran sodium sulfate mice by PEITC and DBM. Carcinogenesis 31:880–885
   PubMed Web of Science ®Google Scholar
• Chung FL, Wang MY, Hecht SS. (1985). Effects of dietary indoles and isothiocyanates on N-nitrosodimethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone alpha-hydroxylation and DNA methylation in rat liver. Carcinogenesis 6:539–543
   PubMed Web of Science ®Google Scholar
• Chung FL, Morse MA, Eklind KI, Lewis J. (1992). Quantitation of human uptake of the anticarcinogen phenethyl isothiocyanate after a watercress meal. Cancer Epidemiol Biomarkers Prev 1:383–388
   PubMed Web of Science ®Google Scholar
• Chung FL, Conaway CC, Rao CV, Reddy BS. (2000). Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate. Carcinogenesis 21:2287–2291
   PubMed Web of Science ®Google Scholar
• Conaway CC, Jiao D, Kohri T, et al. (1999). Disposition and pharmacokinetics of phenethyl isothiocyanate and 6-phenylhexyl isothiocyanate in F344 rats. Drug Metab Dispos 27:13–20
   PubMed Web of Science ®Google Scholar
• Conaway CC, Getahun SM, Liebes LL, et al. (2000). Disposition of glucosinolates and sulforaphane in humans after ingestion of steamed and fresh broccoli. Nutr Cancer 38:168–178
   PubMed Web of Science ®Google Scholar
• Conaway CC, Krzeminski J, Amin S, Chung FL. (2001). Decomposition rates of isothiocyanate conjugates determine their activity as inhibitors of cytochrome p450 enzymes. Chem Res Toxicol 14:1170–1176
   PubMed Web of Science ®Google Scholar
• Conaway CC, Wang CX, Pittman B, et al. (2005). Phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in A/J mice. Cancer Res 65:8548–8557
   PubMed Web of Science ®Google Scholar
• Cramer JM, Teran-Garcia M, Jeffery EH. (2012). Enhancing sulforaphane absorption and excretion in healthy men through the combined consumption of fresh broccoli sprouts and a glucoraphanin-rich powder. Br J Nutr 107:1333–1338
   PubMed Web of Science ®Google Scholar
• Cross JV, Foss FW, Rady JM, et al. (2007). The isothiocyanate class of bioactive nutrients covalently inhibit the MEKK1 protein kinase. BMC Cancer 7:183
   PubMed Web of Science ®Google Scholar
• Dingley KH, Ubick EA, Chiarappa Zucca ML, et al. (2003). Effect of dietary constituents with chemopreventive potential on adduct formation of a low dose of the heterocyclic amines PhIP and IQ and phase II enzymes. Nutr Cancer 46:212–221
   PubMed Web of Science ®Google Scholar
• Eklind KI, Morse MA, Chung FL. (1990). Distribution and metabolism of the natural anticarcinogen phenethyl isothiocyanate in A/J mice. Carcinogenesis 11:2033–2036
   PubMed Web of Science ®Google Scholar
• Epplein M, Wilkens LR, Tiirikainen M, et al. (2009). Urinary isothiocyanates; glutathione S-transferase M1, T1, and P1 polymorphisms; and risk of colorectal cancer: The Multiethnic Cohort Study. Cancer Epidemiol Biomarkers Prev 18:314–320
   PubMed Web of Science ®Google Scholar
• Futakuchi M, Hirose M, Miki T, et al. (1998). Inhibition of DMBA-initiated rat mammary tumour development by 1-O-hexyl-2,3,5-trimethylhydroquinone, phenylethyl isothiocyanate, and novel synthetic ascorbic acid derivatives. Eur J Cancer Prev 7:153–159
   PubMed Web of Science ®Google Scholar
• Gasper AV, Al-Janobi A, Smith JA, et al. (2005). Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. Am J Clin Nutr 82:1283–1291
   PubMed Web of Science ®Google Scholar
• Ghawi SK, Methven L, Niranjan K. (2013). The potential to intensify sulforaphane formation of cooked broccoli (Brassica oleracea var. italica) using mustard seeds (Sinapis alba). Food Chem 138:1734–1741
   PubMed Web of Science ®Google Scholar
• Gill CI, Haldar S, Boyd LA, et al. (2007). Watercress supplementation in diet reduces lymphocyte DNA damage and alters blood antioxidant status in healthy adults. Am J Clin Nutr 85:504–510
   PubMed Web of Science ®Google Scholar
• Gross-Steinmeyer K, Stapleton PL, Liu F, et al. (2004). Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes. Xenobiotica 34:619–632
   PubMed Web of Science ®Google Scholar
• Gross-Steinmeyer K, Stapleton PL, Tracy JH, et al. (2010). Sulforaphane- and phenethyl isothiocyanate-induced inhibition of aflatoxin B1-mediated genotoxicity in human primary hepatocytes: Role of GSTM1 genotype and CYP3A4 gene expression. Toxicol Sci 116:422–432
   PubMed Web of Science ®Google Scholar
• Gum SI, Cho MK. (2013). Differential hepatic GSTA2 expression on arylalkyl isothiocyanates in vivo and in vitro: The molecular mechanism of gene induction by phenethyl isothiocyanate. Mol Nutr Food Res 57:2223–2232
   PubMed Web of Science ®Google Scholar
• Guo Z, Smith TJ, Wang E, et al. (1992). Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats. Carcinogenesis 13:2205–2210
   PubMed Web of Science ®Google Scholar
• Guo Z, Smith TJ, Wang E, et al. (1993). Structure-activity relationships of arylalkyl isothiocyanates for the inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism and the modulation of xenobiotic-metabolizing enzymes in rats and mice. Carcinogenesis 14:1167–1173
   PubMed Web of Science ®Google Scholar
• Gupta P, Kim B, Kim S-H, Srivastava SK. (2014a). Molecular targets of isothiocyanates in cancer: Recent advances. Mol Nutr Food Res 58:1685–1707
   PubMed Web of Science ®Google Scholar
• Gupta P, Wright SE, Kim S-H, Srivastava SK. (2014b). Phenethyl isothiocyanate: A comprehensive review of anti-cancer mechanisms. Biochim Biophys Acta 1846:405–424
   PubMed Web of Science ®Google Scholar
• Hanlon N, Coldham N, Sauer MJ, Ioannides C. (2008a). Up-regulation of the CYP1 family in rat and human liver by the aliphatic isothiocyanates erucin and sulforaphane. Toxicology 252:92–98
   PubMed Web of Science ®Google Scholar
• Hanlon N, Okpara A, Coldham N, et al. (2008b). Modulation of rat hepatic and pulmonary cytochromes P450 and phase II enzyme systems by erucin, an isothiocyanate structurally related to sulforaphane. J Agric Food Chem 56:7866–7871
   PubMed Web of Science ®Google Scholar
• Hanlon N, Coldham N, Gielbert A, et al. (2008c). Absolute bioavailability and dose-dependent pharmacokinetic behaviour of dietary doses of the chemopreventive isothiocyanate sulforaphane in rat. Br J Nutr 99:559–564
   PubMed Web of Science ®Google Scholar
• Hanlon N, Poynton CL, Coldham N, et al. (2009). The aliphatic isothiocyanate erucin and sulforaphane do not effectively up-regulate NAD(P)H:quinone oxidoreductase (NQO1) in human liver compared with rat. Mol Nutr Food Res 53:836–844
   PubMed Web of Science ®Google Scholar
• Hanlon N, Konsue N, Coldham N, et al. (2011). Exposure to isothiocyanates suppresses urinary mutagenicity in rats treated with heterocyclic amine IQ: Lack of association with CYP1 activity. Nutr Cancer 63:300–305
   PubMed Web of Science ®Google Scholar
• Hanschen FS, Bruggemann M, Brodehl A, et al. (2012). Characterization of products from the reaction of glucosinolate-derived isothiocyanates with cysteine and lysine derivatives formed in either model systems or broccoli sprouts. J Agric Food Chem 60:7735–7745
   PubMed Web of Science ®Google Scholar
• Hansson LE, Nyren O, Bergström R, et al. (1993). Diet and risk of gastric cancer: A population-based case-control study in Sweden. Int J Cancer 55:181–189
   PubMed Web of Science ®Google Scholar
• Hayes JD, Kelleher MO, Eggleston IM. (2008). The cancer chemopreventive actions of phytochemicals derived from glucosinolates. Eur J Nutr 47:73–88
   PubMed Web of Science ®Google Scholar
• Hecht SS. (1999). Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. J Nutr 129:768S–774S
   PubMed Web of Science ®Google Scholar
• Hecht SS, Chung FL, Richie JP Jr, et al. (1995). Effects of watercress consumption on metabolism of a tobacco-specific lung carcinogen in smokers. Cancer Epidemiol Biomarkers Prev 4:877–884
   PubMed Web of Science ®Google Scholar
• Hecht SS, Trushin N, Rigotty J, et al. (1996). Complete inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced rat lung tumorigenesis and favorable modification of biomarkers by phenethyl isothiocyanate. Cancer Epidemiol Biomarkers Prev 5:645–652
   PubMed Web of Science ®Google Scholar
• Hecht SS, Carmella SG, Murphy SE. (1999). Effects of watercress consumption on urinary metabolites of nicotine in smokers. Cancer Epidemiol Biomarkers Prev 8:907–913
   PubMed Web of Science ®Google Scholar
• Hecht SS, Trushin N, Chhabra SK, et al. (2000). Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by cultured monkey lung explants. Drug Metab Dispos 28:5–9
   PubMed Web of Science ®Google Scholar
• Hirose M, Yamaguchi T, Kimoto N, et al. (1998). Strong promoting activity of phenylethyl isothiocyanate and benzyl isothiocyanate on urinary bladder carcinogenesis in F344 male rats. Int J Cancer 77:773–777
   PubMed Web of Science ®Google Scholar
• Hofmann T, Kuhnert A, Schubert A, et al. (2009). Modulation of detoxification enzymes by watercress: In vitro and in vivo investigations in human peripheral blood cells. Eur J Nutr 48:483–491
   PubMed Web of Science ®Google Scholar
• Hu K, Morris ME. (2004). Effects of benzyl-, phenethyl-, and alpha-naphthyl isothiocyanates on P-glycoprotein- and MRP1-mediated transport. J Pharm Sci 93:1901–1911
   PubMed Web of Science ®Google Scholar
• Huang Q, Lawson TA, Morris CR, Mervish SS. (1993). Inhibition by phenylethyl and phenylhexyl isothiocyanate of metabolism of and DNA methylation by N-nitrosomethylamylamine in rats. Carcinogenesis 14:749–754
   PubMed Web of Science ®Google Scholar
• Ioannides C. (2002). Pharmacokinetic interactions between herbal remedies and medicinal drugs. Xenobiotica 32:451–478
   PubMed Web of Science ®Google Scholar
• Ioannides C. (2013). Up-regulation of cytochrome P450 and phase II enzymes by xenobiotics in precision-cut tissue slices. Xenobiotica 43:15–28
   PubMed Web of Science ®Google Scholar
• Ioannides C, Lewis DFV. (2004). Cytochromes P450 in the bioactivation of chemicals. Curr Top Med Chem 4:1767–1788
   PubMed Web of Science ®Google Scholar
• Ishizaki H, Brady JF, Ning SM, Yang CS. (1990). Effect of phenethyl isothiocyanate on microsomal N-nitrosodimethylamine metabolism and other monooxygenase activities. Xenobiotica 20:255–264
   PubMed Web of Science ®Google Scholar
• Ji Y, Morris ME. (2003). Determination of phenethyl isothiocyanate in human plasma and urine by ammonia derivatization and liquid chromatography-tandem mass spectrometry. Anal Biochem 323:39–47
   PubMed Web of Science ®Google Scholar
• Ji Y, Morris ME. (2005a). Transport of dietary phenethyl isothiocyanate is mediated by multidrug resistance protein 2 but not P-glycoprotein. Biochem Pharmacol 70:640–647
   PubMed Web of Science ®Google Scholar
• Ji Y, Morris ME. (2005b). Membrane transport of dietary phenethyl isothiocyanate by ABCG2 (breast cancer resistance protein). Mol Pharm 2:414–419
   PubMed Web of Science ®Google Scholar
• Ji Y, Kuo Y, Morris ME. (2005). Pharmacokinetics of dietary phenethyl isothiocyanate in rats. Pharm Res 22:1658–1666
   PubMed Web of Science ®Google Scholar
• Jiao D, Eklind KI, Choi CI, et al. (1994). Structure-activity relationships of isothiocyanates as mechanism-based inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice. Cancer Res 54:4327–4333
   PubMed Web of Science ®Google Scholar
• Jiao D, Conaway CC, Wang MH, et al. (1996). Inhibition of N-nitrosodimethylamine demethylase in rat and human liver microsomes by isothiocyanates and their glutathione, l-cysteine, and N-acetyl-l-cysteine conjugates. Chem Res Toxicol 9:932–938
   PubMed Web of Science ®Google Scholar
• Jiao D, Smith TJ, Yang CS, et al. (1997). Chemopreventive activity of thiol conjugates of isothiocyanates for lung tumorigenesis. Carcinogenesis 18:2143–2147
   PubMed Web of Science ®Google Scholar
• Kall MA, Vang O, Clausen J. (1996). Effects of dietary broccoli in human in vivo drug metabolizing enzymes: Evaluation of caffeine, oestrone and chlorzoxazone metabolism. Carcinogenesis 17:793–799
   PubMed Web of Science ®Google Scholar
• Kassie F, Knasmüller S. (2000). Genotoxic effects of allyl isothiocyanate (AITC) and phenethyl isothiocyanate (PEITC). Chem Biol Interact 127:163–180
   PubMed Web of Science ®Google Scholar
• Keum YS, Owuor ED, Kim BR, et al. (2003). Involvement of Nrf2 and JNK1 in the activation of antioxidant responsive element (ARE) by chemopreventive agent phenethyl isothiocyanate (PEITC). Pharm Res 20:1351–1356
   PubMed Web of Science ®Google Scholar
• Khor TO, Cheung WK, Prawan A, et al. (2008). Chemoprevention of familial adenomatous polyposis in Apc(Min/+) mice by phenethyl isothiocyanate (PEITC). Mol Carcinogen 47:321–325
   PubMed Web of Science ®Google Scholar
• Kim RB, Wilkinson GR. (1996). Watercress inhibits human CYP2E1 activity in vivo as measured by chlorzoxazone 6-hydroxylation. Clin Pharmacol Ther 59:170
   Google Scholar
• Konsue N, Ioannides C. (2008). Tissue differences in the modulation of rat cytochromes P450 and phase II conjugation systems by dietary doses of phenethyl isothiocyanate. Food Chem Toxicol 46:3677–3683
   PubMed Web of Science ®Google Scholar
• Konsue N, Ioannides C. (2010a). Modulation of carcinogen-metabolising cytochromes P450 in human liver by the chemopreventive phytochemical phenethyl isothiocyanate, a constituent of cruciferous vegetables. Toxicology 268:184–190
   PubMed Web of Science ®Google Scholar
• Konsue N, Ioannides C. (2010b). Phenethyl isocyanate is not the metabolite of phenethyl isothiocyanate responsible for mechanism-based inhibition of cytochrome P450. Arch Toxicol 84:751–759
   PubMed Web of Science ®Google Scholar
• Konsue N, Ioannides C. (2010c). Differential response of four human livers to modulation of phase II enzyme systems by the chemopreventive phytochemical phenethyl isothiocyanate. Mol Nutr Food Res 54:1477–1485
   PubMed Web of Science ®Google Scholar
• Konsue N, Kirkpatrick J, Kuhnert N, et al. (2010). Repeated oral administration modulates the pharmacokinetic behaviour of the chemopreventive agent phenethyl isothiocyanate in rats. Mol Nutr Food Res 54:426–432
   PubMed Web of Science ®Google Scholar
• Lake BG, Price RJ. (2013). Evaluation of the metabolism and hepatotoxicity of xenobiotics utilizing precision-cut slices. Xenobiotica 43:41–53
   PubMed Web of Science ®Google Scholar
• La Marca M, Beffy P, Della Croce C, et al. (2012). Structural influence of isothiocyanates on expression of cytochrome P450, phase II enzymes, and activation of Nrf2 in primary rat hepatocytes. Food Chem Toxicol 50:2822–2830
   PubMed Web of Science ®Google Scholar
• Leclercq I, Desager JP, Horsmans Y. (1998). Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress. Clin Pharmacol Ther 64:144–149
   PubMed Web of Science ®Google Scholar
• Lam TK, Gallicchio L, Lindsley K, et al. (2009). Cruciferous vegetable consumption and lung cancer risk: A systematic review. Cancer Epidemiol Biomarkers Prev 18:184–195
   PubMed Web of Science ®Google Scholar
• Lee MS. (1996). Enzyme induction and comparative oxidative desulfuration of isothiocyanates to isocyanates. Chem Res Toxicol 9:1072–1078
   PubMed Web of Science ®Google Scholar
• Liebes L, Conaway CC, Hochster H, et al. (2001). High-performance liquid chromatography-based determination of total isothiocyanate levels in human plasma: Application to studies with 2-phenethyl isothiocyanate. Anal Biochem 291:279–289
   PubMed Web of Science ®Google Scholar
• Lin JM, Amin S, Trushin N, Hecht SS. (1993). Effects of isothiocyanates on tumorigenesis by benzo[a]pyrene in murine tumor models. Cancer Lett 74:151–159
   PubMed Web of Science ®Google Scholar
• Lubet RA, Steele VE, Eto I, et al. (1997). Chemopreventive efficacy of anethole trithione, N-acetyl-l-cysteine, miconazole and phenethyl isothiocyanate in the DMBA-induced rat mammary cancer model. Int J Cancer 72:95–101
   PubMed Web of Science ®Google Scholar
• Maertens LA, Upadhyaya P, Hecht SS, Zimmerman CL. (2010). Formation and distribution of NNK metabolites in an isolated perfused rat lung. Drug Metab Dispos 38:752–760
   PubMed Web of Science ®Google Scholar
• Manson MM, Ball HW, Barrett MC, et al. (1997). Mechanism of action of dietary chemoprotective agents in rat liver: Induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism. Carcinogenesis 18:1729–1738
   PubMed Web of Science ®Google Scholar
• McDanell RE, Henderson LA, Russell K, Mclean AEM. (1992). The effect of Brassica vegetable consumption on caffeine metabolism in humans. Hum Exp Toxicol 11:167–172
   PubMed Web of Science ®Google Scholar
• Meyer DJ, Crease DJ, Ketterer B. (1995). Forward and reverse catalysis and product sequestration by human glutathione S-transferases in the reaction of GSH with dietary aralkyl isothiocyanates. Biochem J 306:565–569
   PubMed Web of Science ®Google Scholar
• Mi L, Wang X, Govind S, et al. (2007). The role of protein binding in induction of apoptosis by phenethyl isothiocyanate and sulforaphane in human non-small lung cancer cells. Cancer Res 67:6409–6416
   PubMed Web of Science ®Google Scholar
• Morris CR, Chen SC, Zhou L, et al. (2004). Inhibition by allyl sulfides and phenethyl isothiocyanate of methyl-n-pentylnitrosamine depentylation by rat esophageal microsomes, human and rat CYP2E1, and rat CYP2A3. Nutr Cancer 48:54–63
   PubMed Web of Science ®Google Scholar
• Morse MA, Wang CX, Stoner GD, et al. (1989). Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced DNA adduct formation and tumorigenicity in the lung of F344 rats by dietary phenethyl isothiocyanate. Cancer Res 49:549–553
   PubMed Web of Science ®Google Scholar
• Morse MA, Eklind KI, Amin SG, Chung FL. (1992). Effect of frequency of isothiocyanate administration on inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary adenoma formation in A/J mice. Cancer Lett 62:77–81
   PubMed Web of Science ®Google Scholar
• Morse MA, Lu J, Stone GD, et al. (1999). Metabolism of N-nitrosobenzylmethylamine by human cytochrome P-450 enzymes. J Toxicol Environ Health A 58:397–411
   PubMed Web of Science ®Google Scholar
• Morse MA, Zu H, Galati AJ, et al. (1993). Dose-related inhibition by dietary phenethyl isothiocyanate of esophageal tumorigenesis and DNA methylation induced by N-nitrosomethylbenzylamine in rats. Cancer Lett 72:103–110
   PubMed Web of Science ®Google Scholar
• Murata M, Yamashita N, Inoue S, Kawanishi S. (2000). Mechanism of oxidative DNA damage induced by carcinogenic allyl isothiocyanate. Free Radic Biol Med 28:797–805
   PubMed Web of Science ®Google Scholar
• Murray S, Lake BG, Gray S, et al. (2001). Effect of cruciferous vegetable consumption on heterocyclic aromatic amine metabolism in man. Carcinogenesis 22:1413–1420
   PubMed Web of Science ®Google Scholar
• Musk SR, Johnson IT. (1993). The clastogenic effects of isothiocyanates. Mutat Res 300:111–117
   PubMed Web of Science ®Google Scholar
• Musk SR, Smith TK, Johnson IT. (1995). On the cytotoxicity and genotoxicity of allyl and phenethyl isothiocyanates and their parent glucosinolates sinigrin and gluconasturtiin. Mutat Res 348:19–23
   PubMed Web of Science ®Google Scholar
• Nakajima M, Yoshida R, Shimada N, et al. (2001). Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate. Drug Metab Dispos 29:1110–1113
   PubMed Web of Science ®Google Scholar
• Nishikawa A, Furukawa F, Uneyama C, et al. (1996). Chemopreventive effects of phenethyl isothiocyanate on lung and pancreatic tumorigenesis in N-nitrosobis(2-oxopropyl)amine-treated hamsters. Carcinogenesis 17:1381–1384
   PubMed Web of Science ®Google Scholar
• Ogawa K, Hirose M, Sugiura S, et al. (2001). Dose-dependent promotion by phenylethyl isothiocyanate, a known chemopreventer, of two-stage rat urinary bladder and liver carcinogenesis. Nutr Cancer 40:134–139
   PubMed Web of Science ®Google Scholar
• Pantuck EJ, Pantuck CB, Garland WA, et al. (1979). Stimulatory effect of Brussel sprouts and cabbage on human drug metabolism. Clin Pharmacol Ther 25:88–95
   PubMed Web of Science ®Google Scholar
• Pantuck EJ, Pantuck CB, Anderson KE, et al. (1984). Effect of brussels sprouts and cabbage on drug conjugation. Clin Pharmacol Ther 35:161–169
   PubMed Web of Science ®Google Scholar
• Pereira MA. (1995). Chemoprevention of dimethylnitrosamine-induced liver foci and hepatocellular adenomas in C3H mice. Anticancer Res 15:1953–1956
   PubMed Web of Science ®Google Scholar
• Plate AY, Gallaher DD. (2006). Effects of indole-3-carbinol and phenethyl isothiocyanate on colon carcinogenesis induced by azoxymethane in rats. Carcinogenesis 27:287–292
   PubMed Web of Science ®Google Scholar
• Powolny AA, Bommareddy A, Hahm ER, et al. (2011). Chemopreventive potential of the cruciferous vegetable constituent phenethyl isothiocyanate in a mouse model of prostate cancer. J Natl Cancer Inst 103:571–584
   PubMed Web of Science ®Google Scholar
• Reen RK, Dombkowski AA, Kresty LA, et al. (2007). Effects of phenethyl isothiocyanate on early molecular events in N-nitrosomethylbenzylamine-induced cytotoxicity in rat esophagus. Cancer Res 67:1684–1692
   Web of Science ®Google Scholar
• Rendic S, Guengerich FP. (2012). Contributions of human enzymes in carcinogen metabolism. Chem Res Toxicol 25:1316–1383
   PubMed Web of Science ®Google Scholar
• Seo KW, Kim JG, Park M, et al. (2000). Effects of phenethylisothiocyanate on the expression of glutathione S-transferases and hepatotoxicity induced by acetaminophen. Xenobiotica 30:535–545
   PubMed Web of Science ®Google Scholar
• Siglin, JC, Barch DH, Stoner GD. (1995). Effects of dietary phenethyl isothiocyanate, ellagic acid, sulindac and calcium on the induction and progression of N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats. Carcinogenesis 16:1101–1106
   PubMed Web of Science ®Google Scholar
• Singh SV, Kim SH, Sehrawat A, et al. (2012). Biomarkers of Phenethyl-isothiocyanate-mediated mammary cancer chemoprevention in a clinically relevant mouse model. J Natl Cancer Inst 104:1228–1239
   PubMed Web of Science ®Google Scholar
• Smith TJ, Guo Z, Li C, et al. (1993). Mechanisms of inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bioactivation in mouse by dietary phenethyl isothiocyanate. Cancer Res 53:3276–3282
   PubMed Web of Science ®Google Scholar
• Smith TJ, Guo Z, Guengerich FP, Yang CS. (1996). Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by human cytochrome P450 1A2 and its inhibition by phenethyl isothiocyanate. Carcinogenesis 17:809–813
   PubMed Web of Science ®Google Scholar
• Solt DB, Chang K, Helenowski I, Rademaker AW. (2003). Phenethyl isothiocyanate inhibits nitrosamine carcinogenesis in a model for study of oral cancer chemoprevention. Cancer Lett 202:147–152
   PubMed Web of Science ®Google Scholar
• Song L, Morrison JJ, Botting NP, Thornalley PJ. (2005). Analysis of glucosinolates, isothiocyanates, and amine degradation products in vegetable extracts and blood plasma by LC-MS/MS. Anal Biochem 347:234–243
   PubMed Web of Science ®Google Scholar
• Staack R, Kingston S, Wallig MA, Jeffery EH. (1998). A comparison of the individual and collective effects of four glucosinolate breakdown products from brussels sprouts on induction of detoxification enzymes. Toxicol Appl Pharmacol 149:17–23
   PubMed Web of Science ®Google Scholar
• Staretz ME, Hecht SS. (1995). Effects of phenethyl isothiocyanate on the tissue distribution of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and metabolites in F344 rats. Cancer Res 55:5580–5588
   PubMed Web of Science ®Google Scholar
• Staretz ME, Koenig LA, Hecht SS. (1997a). Effects of long term dietary phenethyl isothiocyanate on the microsomal metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in F344 rats. Carcinogenesis 18:1715–1722
   PubMed Web of Science ®Google Scholar
• Staretz MA, Foiles PG, Miglietta LM, Hecht SS. (1997b). Evidence for the important role of DNA pyridyloxobutylation in rat lung carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone: Effects of dose and phenethyl isothiocyanate. Cancer Res 57:259–266
   PubMed Web of Science ®Google Scholar
• Steinbrecher A, Linseisen L. (2009). Dietary intake of individual glucosinolates in participants of the EPIC-Heidelberg cohort study. Ann Nutr Metab 54:87–96
   PubMed Web of Science ®Google Scholar
• Steinbrecher A, Nimptsch K, Husing A, et al. (2009). Dietary glucosinolate intake and risk of prostate cancer in the EPIC-Heidelberg cohort study. Int J Cancer 125:2179–2186
   PubMed Web of Science ®Google Scholar
• Sticha KR, Staretz ME, Wang M, et al. (2000). Effects of benzyl isothiocyanate and phenethyl isothiocyanate on benzo[a]pyrene metabolism and DNA adduct formation in the A/J mouse. Carcinogenesis 21:1711–1719
   PubMed Web of Science ®Google Scholar
• Sticha KRK, Kenney PMJ, Boysen K, et al. (2002). Effects of benzyl isothiocyanate and phenethyl isothiocyanate on a DNA adduct formation by a mixture of benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mouse lung. Carcinogenesis 23:1433–1439
   PubMed Web of Science ®Google Scholar
• Stoner GD, Kresty LA, Carlton PS, et al. (1999). Isothiocyanates and freeze-dried strawberries as inhibitors of esophageal cancer. Toxicol Sci 52:95–100
   PubMed Web of Science ®Google Scholar
• Stoner GD, Morrissey DT, Heur YH, et al. (1991). Inhibitory effects of phenethyl isothiocyanate on N-nitrosobenzylmethylamine carcinogenesis in the rat esophagus. Cancer Res 51:2063–2068
   PubMed Web of Science ®Google Scholar
• Szaefer H, Krajka-Kuźniak V, Bartoszek A, Baer-Dubowska W. (2012). Modulation of carcinogen-metabolizing cytochromes P450 in rat liver and kidney by cabbage and sauerkraut juices: Comparison with the effects of indole-3-carbinol and phenethyl isothiocyanate. Phytother Res 26:1148–1155
   PubMed Web of Science ®Google Scholar
• Telang U, Ji Y, Morris ME. (2009). ABC transporters and isothiocyanates: Potential for pharmacokinetic diet-drug interactions. Biopharm Drug Interact 30:335–344
   PubMed Web of Science ®Google Scholar
• van Lieshout EM, Peters WH, Jansen JB. (1996). Effect of oltipraz, alpha-tocopherol, beta-carotene and phenethylisothiocyanate on rat oesophageal, gastric, colonic and hepatic glutathione, glutathione S-transferase and peroxidase. Carcinogenesis 17:1439–1445
   PubMed Web of Science ®Google Scholar
• Verhoeven DT, Verhagen H, Goldbohm RA, et al. (1997). A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chem Biol Interact 103:79–129
   PubMed Web of Science ®Google Scholar
• Vermeulen M, van den Berg R, Friedig AP, et al. (2006). Association between consumption of cruciferous vegetables and condiments and excretion in urine of isothiocyanate mercapturic acids. J Agric Food Chem 54:5350–5358
   PubMed Web of Science ®Google Scholar
• Vistisen K, Poulsen HE, Loft S. (1992). Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. Carcinogenesis 13:1561–1568
   PubMed Web of Science ®Google Scholar
• von Weymarn LB, Chun JA, Hollenberg PF. (2006). Effects of benzyl and phenethyl isothiocyanate on P450s 2A6 and 2A13: Potential for chemoprevention in smokers. Carcinogenesis 27:782–790
   PubMed Web of Science ®Google Scholar
• Wallig MA, Kingston S, Staack R, Jeffery EH. (1998). Induction of rat pancreatic glutathione S-transferase and quinone reductase activities by a mixture of glucosinolate breakdown derivatives found in Brussels sprouts. Food Chem Toxicol 36:365–373
   PubMed Web of Science ®Google Scholar
• Walters DG, Young PJ, Agus C, et al. (2004). Cruciferous vegetable consumption alters the metabolism of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans. Carcinogenesis 25:1659–1669
   PubMed Web of Science ®Google Scholar
• Wang LG, Chiao JW. (2010). Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review). Int J Oncol 37:533–539
   PubMed Web of Science ®Google Scholar
• Wattenberg LW. (1977). Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J Natl Cancer Inst 58:395–398
   PubMed Web of Science ®Google Scholar
• Wilkinson JT, Morse MA, Kresty LA, Stoner GD. (1995). Effect of alkyl chain length on inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis and DNA methylation by isothiocyanates. Carcinogenesis 16:1011–1015
   PubMed Web of Science ®Google Scholar
• Witschi H, Espiritu I, Yu M, Willits NH. (1998). The effects of phenethyl isothiocyanates, N-acetylcysteine and green tea on tobacco smoke-induced lung tumors in strain A/J mice. Carcinogenesis 19:1789–1794
   PubMed Web of Science ®Google Scholar
• Xu C, Yuan X, Pan Z, et al. (2006). Mechanism of action of isothiocyanates: The induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2. Mol Cancer Ther 5:1918–1926
   PubMed Web of Science ®Google Scholar
• Yang YM, Conaway CC, Chiao JW, et al. (2002). Inhibition of benzo(a)pyrene-induced lung tumorigenesis by dietary N-acetylcysteine conjugates of benzyl and phenethyl isothiocyanates during the postinitiation phase is associated with activation of mitogen-activated protein kinases and p53 activity and induction of apoptosis. Cancer Res 62:2–7
   PubMed Web of Science ®Google Scholar
• Yoshigae Y, Sridar C, Kent UM, Hollenberg PF. (2013). The inactivation of human CYP2E1 by phenethyl isothiocyanate, a naturally-occurring chemopreventive agent, and its oxidative bioactivation. Drug Metab Dispos 41:858–869
   PubMed Web of Science ®Google Scholar
• Yoxall V, Kentish P, Coldham N, et al. (2005). Modulation of hepatic cytochrome P450 and phase II enzymes by dietary doses of sulforaphane in rats: Implications for its chemopreventive activity. Int J Cancer 117:356–362
   PubMed Web of Science ®Google Scholar
• Zhang Y. (2012). The molecular basis that unifies the metabolism, cellular uptake and chemopreventive activities of dietary isothiocyanates. Carcinogenesis 33:2–9
   PubMed Web of Science ®Google Scholar
• Zhang Y, Callaway EC. (2002). High cellular accumulation of sulphoraphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. Biochem J 364:301–307
   PubMed Web of Science ®Google Scholar
• Zhang Y, Talalay P. (1994). Anticarcinogenic activities of organic isothiocyanates: Chemistry and mechanisms. Cancer Res 54:1976s–1981s
   PubMed Web of Science ®Google Scholar